Circuit-specific cell types in aging and Alzheimer's disease

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Abstract The long-term goal of this project is to define and identify circuit-specific cell types–cellular scale connectome– that are selectively vulnerable to loss of cell bodies or axonal connections or change of transcriptomic signatures of individual neurons during the progression of healthy aging and Alzheimer's disease (AD). Evidence suggests that knowledge on the change of cellular scale connectomes–cell type-specific circuits by coupling single cell transcriptome with brain connectivity– is needed for holistic understanding of aging and AD and provides an experimentally tractable basis to address longitudinal changes. These aging- and AD- associated changes may include loss of cell types, connectivity or alterations in transcriptomic signatures. This approach employed here is to test the hypothesis that there are aging- or AD state-specific neural and molecular circuits that drive the progression of aging and AD. A large body of evidence demonstrates that AD is a heterogeneous, multifactorial disease that selectively affects certain brain regions, e.g. the entorhinal cortex (EC), while other areas, such as the cerebellum, remain unaffected. Recent studies on the staging of AD neuropathology showed AD-related neuropathology begins in the locus coeruleus (LC) or the EC, followed by the hippocampus (HC) and then the prefrontal cortex (PFC). The LC contains both adrenergic (NA) and non- noradrenergic neurons and provides the major NA inputs throughout the entire brain. Neuropathological staging has shown that tangles fist appear in the LC and NA activation has been shown to ameliorate AD deficits. The EC provides key cortical inputs to the HC, which is essential in learning memory. The PFC provides the top-down regulation on various higher order functions. But cell types-based input and/or output networks that are selectively vulnerable at the single neurons level are not well understood. As aging is a major risk factor for AD, it is important to understand whether there are distinct, similar or overlapping selectively vulnerable circuit-specific cell types between aging and AD. This project is to combine retrograde labeling with multiomic sn-RNAseq and sn-ATACseq to link transcriptomic and epigenomic properties of cell types to neuronal projections and investigate circuit-specific changes associated with progression of aging and AD in four brain regions, namely the LC, EC, HC and PFC, in both male and female control and AD mice. For AD mice, the APPNLF mouse line–that carries knockin human mutations in the amyloid precursor protein gene and, importantly, expresses physiological levels of Aβ, mimicking late onset AD–will be used. The data from this project will provide novel insights on the types of neurons vulnerable to degeneration and/or alterations of molecular/signaling signature networks in a spatial and temporal fashion and the correlation with neuropathology and cognitive impairment. This approach is a major step toward establishing multiscale models that will help to fill the gap between the effects of genetic variants (e.g., APP, AOPE or TREM2) on brain topology with molecular networks in aging and AD.